The present invention concerns the heterocyclic carbon compounds of the 1,4-dihydropyridine class with a 3-carboxylate or carboxamido group linked to an arylpiperazinylalkylene moiety. These compounds possess bio-affecting properties.
A substantial body of prior art has evolved over the last decade involving compounds of 4-aryl-1,4-dihydropyridine series which have calcium antagonist properties and are useful in the treatment of cardiovascular diseases. These calcium blocking effects appear to mediate vasodilation making these compounds useful in treating angina and hypertension. These structures are typified by nifedipine. (Formula 1); ##STR2## chemically 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine. Nifedipine and some related 4-aryl-1,4-dihydropyridines are the subject of U.S. Pat. No. 3,485,847 issued Dec. 23, 1969. Numerous subsequent patent have been granted covering 1,4-dihydropyridines in which other substituent groups have been incorporated at the various ring positions of the dihydropyridine moiety via a diversity of chemical bonding groups.
Utilizing medicinal chemical techniques, an object of the instant invention was to design a therapeutic agent combining .alpha..sub.1 -adrenergic blocking properties with the calcium blocking action in a single molecular structure. The biological rationale for the combination of actions suggests that such an agent would provide potent and efficacious treatment for vasospastic circulatory disorders.
Art related to the series of compounds of the present invention may be generalized by the following structural formula (2): ##STR3## wherein R.sup.2, R.sup.4, R.sup.5 and R.sup.6 could be any of a number of substituent groups which have been defined previously in the voluminous dihydropyridine literature; but with specific attention being given the definition for the substituent structure attached to the 3-position of the 1,4-dihydropyridine ring. To our knowledge, no aryl- or hetaryl-piperazinylalkyl moiety has been incorporated heretofore in a 1,4-dihydropyridine ring compound via a carboxylate amide or ester functionality in the 3-position of the ring. The most relevant art to be disclosed is, in our judgment, the divisional patents, U.S. Pat. No. 3,905,970 and U.S. Pat. No. 3,974,275 issued to Bossert, et al., on Sept. 16, 1975, and Aug. 10, 1976, respectively. The compounds disclosed and claimed in these patents have as the 3-substituent side chain moiety ##STR4## shown in structure (2) above, the following (2a): ##STR5##
This same 3-substituent side chain (2a) was also disclosed in U.S. Pat. No. 4,393,070 issued to Sato, et al., on July, 1983.
European Patent Application No. 88,903, published Sept. 21, 1983 discloses 1,4-dihydropyridine art with the ester group of the 3-carboxylate moiety having the following structure (2b): ##STR6## wherein n is 0 to 5; Z is aryl or hetaryl; and R is lower alkyl, alkoxycarbonyl, or alkanoylamino. The point of novelty disclosed for these antihypertensive agents is based on Z, in that " . . . the introduction of the aromatic ring or aromatic heterocyclic ring at alpha-position of the cyclic amino alkyl ester moiety in the side chain causes increased and remarkably prolonged effectiveness."
Somewhat less related, European Patent Application No. 63,365, published Oct. 27, 1982 discloses 1,4-dihydropyridines with a 3-carboxylate ester group comprising a piperidine ring (3): ##STR7## wherein n is 0 to 3, and R.sup.5 is arylalkyl or acyl.
Additionally, there are 1,4-dihydropyridine compounds disclosed which have an arylpiperazine system attached by an alkyl or alkoxyalkyl chain to the 2-position of the dihydropyridine ring. Aritomi, et al., in Chem. Pharm. Bull. 29 (11), 3163-71 (1980) disclose compounds having the (4) group in ring position 2: ##STR8## wherein n=2 and R is alkyl, aryl, or arylalkyl. Specifically disclosed, as an example, is compound (4a). ##STR9##
European Patent Application No. 60,674, published Sept. 22, 1982 discloses anti-ischemic and antihypertensive agents of structure (5) ##STR10## wherein Y is an ethylene or propylene chain; and R.sup.5 is C.sub.1-4 alkyl, aryl, arylalkyl, and the like. These compounds are easily distinguished structurally from the compounds of the instant invention by virtue of ring position and the linking functional group. That is, compounds of the instant invention contain an .alpha.-blocking aryl- or hetaryl piperazine moiety linked by an alkyl, alkoxyalkyl, or alkylaminoalkyl chain to a carboxylate or carboxamide function in ring position 3.
All of the above mentioned compounds derive their therapeutic usefulness, according to prevailing theory of their biological mechanism, due to their inate ability to act as calcium channel blockers. In essence, the instant compounds may be distinguished over compounds of the prior art both on the basis of molecular structure and also by biological action. The instant compounds possess both calcium channel and alpha-adrenergic blocking properties, thereby enhancing the usefulness of these compounds in treating hypertension and ischemic disorders. The instant compounds have also been found to possess useful actions in inhibiting certain functions of blood platelets. There is nothing in the prior art which anticipates or suggests the compounds of the present invention.